Dementia Collaborative Research Centre

The complex and multilevel nature of health has made it challenging to evaluate public health actions. Performing comparative analyses in different contexts is particularly challenging. Health care associated infections are a public health threat in need of more effective hospital infection control. They are associated with significant morbidity and mortality worldwide and place a large burden on health care resources. Hospital infection control has had mixed success, with many aspects of context playing a large role. As such, systems approaches are called for that improve the capability to capture multilevel determinants, context and complex and causal interrelationships (such as feedback and nonlinearity) that may change over time.

In this thesis a novel ‘multilevel systems approach’ is proposed that appears capable of complex, multilevel and causal analysis. The approach draws together qualitative and quantitative concepts and methods from four multilevel systems theories and methodologies: the Realist approach, Systems Thinking, Health System Frameworks and System Modelling and Simulation. The power and feasibility of the approach to analyse and evaluate complex public health actions in different contexts is examined by its specific application to hospital infection control. In particular, to the control of Methicillin-resistant Staphylococcus aureus (MRSA), a health care associated multidrug-resistant infection.

In doing so, the context-specific (and nonlinear) effects of competing hospital infection control policies on changing trends in the incidence rate and prevalence of MRSA were measured and compared. The capability to evaluate multiple infection control policies implemented in different and interacting ward settings simultaneously, had not previously been demonstrated. This subsequently provided valuable insights. Given the contribution and generalisability of the multilevel systems approach, its application toward a range of public health actions is recommended.

The model can be viewed here: http://www.runthemodel.com/models/1055/

Ex vivo expansion of cord blood cells generally results in reduced stem cell activity in vivo. Glycogen synthase kinase-3beta (GSK-3beta) regulates the degradation of beta-catenin, a critical regulator of hematopoietic stem cells (HSCs). Here we show that GSK-3beta inhibition activates beta-catenin in cord blood CD34(+) cells and upregulates beta-catenin transcriptional targets c-myc and HoxB4, both known to regulate HSC self-renewal. GSK-3beta inhibition resulted in delayed ex vivo expansion of CD34(+) cells, yet enhanced the preservation of stem cell activity as tested in long-term culture with bone marrow stroma. Delayed cell cycling, reduced apoptosis, and increased adherence of hematopoietic progenitor cells to bone marrow stroma were observed in these long-term cultures treated with GSK-3beta inhibitor. This improved adherence to stroma was mediated via upregulation of CXCR4. In addition, GSK-3beta inhibition preserved severe combined immunodeficiency (SCID) repopulating cells as tested in the nonobese diabetic/SCID mouse model. Our data suggest the involvement of GSK-3beta inhibition in the preservation of HSC and their interaction with the bone marrow environment. Methods for the inhibition of GSK-3beta may be developed for clinical ex vivo expansion of HSC for transplantation. In addition, GSK-3beta inhibition suppressed leukemic cell growth via the induction of apoptosis mediated by the downregulation of survivin. Modulators of GSK-3beta may increase the range of novel drugs that specifically kill leukemic cells while sparing normal stem cells.

Glycogen synthase kinase-3β (GSK-3β) has been identified as an important regulator of stem cell function acting through activation of the wingless (Wnt) pathway. Here, we report that treatment with an inhibitor of GSK-3β, 6-bromoindirubin 3'-oxime (BIO) delayed cell cycle progression by increasing cell cycle time. BIO treatment resulted in the accumulation of late dividing cells enriched with primitive progenitor cells retaining the ability for sustained proliferation. In vivo analysis using a Non-obese diabetic/severe combined immunodeficient (NOD/SCID) transplantation model has demonstrated that pretreatment with BIO promotes engraftment of ex vivo-expanded hematopoietic stem cells. BIO enhanced the engraftment of myeloid, lymphoid and primitive stem cell compartments. Limiting dilution analysis of SCID repopulating cells (SRC) revealed that BIO treatment increased human chimerism without increasing SRC frequency. Clonogenic analysis of human cells derived from the bone marrow of transplant recipient mice demonstrated that a higher level of human chimerism and cellularity was related to increased regeneration per SRC unit. Gene expression analysis showed that treatment with BIO did not modulate the expression of canonical Wnt target genes upregulated during cytokine-induced cell proliferation. BIO increased the expression of several genes regulating Notch and Tie2 signaling downregulated during ex vivo expansion, suggesting a role in improving stem cell engraftment. In addition, treatment with BIO upregulated CDK inhibitor p57 and downregulated cyclin D1, providing a possible mechanism for the delay seen in cell cycle progression. We conclude that transient, pharmacologic inhibition of GSK-3β provides a novel approach to improve engraftment of expanded HSC after stem cell transplantation.

Interferon regulatory factor (IRF) 1 and its functional antagonist IRF2 were originally discovered as transcription factors that regulate the interferon-beta gene. Control of cell growth has led to the definition of IRF1 as a tumour suppressor gene and IRF2 as an oncogene. Clinically, approximately 70% of cases of acute myeloid leukaemia demonstrate dysregulated expression of IRF1 and/or IRF2. Our previous studies have shown that human leukaemic TF-1 cells exhibit abnormally high expression of both IRF1 and IRF2, the latter acting to abrogate IRF1 tumour suppression, making these cells ideal for analysis of down-regulation of IRF2 expression. A novel G418 screening protocol was developed and used for identifying effective siRNA that targets IRF2 (siIRF2). Using optimized siIRF2 in leukaemic TF-1 cells, IRF2 was down-regulated by approximately 70% at both mRNA and protein levels. Phenotypically, this resulted in growth inhibition associated with G2/M arrest as well as induction of polyploidy, differentiation and apoptosis. In contrast to these results, siIRF2 targeting did not affect normal haematopoietic stem/progenitor cell growth. These results indicate the potential utility of IRF2 inhibition as a therapeutic approach to cancer.

ABSTRACT Glycogen synthase kinase 3 beta (GSK-3 beta) was one of the first kinases identified and studied, initially for its role in the regulation of glycogen synthesis. Over the past decade, interest in GSK-3 beta has grown far beyond glycogen metabolism, and this is due in large measure to the critical role that GSK-3 beta plays in the regulation of many other cellular processes, particularly cell proliferation and apoptosis. GSK-3 beta has been shown to regulate the proteolysis and sub-cellular compartmentalization of a number of proteins directly involved in the regulation of cell cycling, proliferation, differentiation and apoptosis. GSK-3 beta also regulates the degradation of proteins that regulate gene expression and thus affects a variety of important cell functions. Specifically, GSK-3 beta controls the degradation of beta-catenin, the main effector of Wnt that regulates haematopoiesis and stem cell function. In this case GSK-3 beta is a negative regulator of Wnt. In contrast, GSK-3 beta positively regulates NF-kappa B, another important biochemical pathway also involved in the regulation of multiple aspects of normal and aberrant haematopoiesis. GSK-3 beta regulates degradation of I kappa B, a central inhibitor of NF-kappa B. In this way, GSK-3 beta acts to control the resistance of leukaemic cells to chemotherapy through the modulation of NF-kappa B, a critical factor in maintaining leukaemic cell growth. In addition, GSK-3 beta regulates the pro-inflammatory activity of NF-kappa B. As GSK-3 beta is a pleiotropic regulator, inhibitors may increase the range of novel anti-leukaemic and anti-inflammatory drugs that control immune response.

Antipsychotic and other tranquilising medicines are prescribed to help care staff manages behaviour in one-quarter of older people living in Australian long-term care homes. While these medicines pose significant health risks, particularly for people with dementia, reliance on their use occurs when staff are not educated to respond to resident behaviour using nonpharmacological approaches. The Halting Antipsychotic use in Long-Term care (HALT) single-arm study was undertaken to address this issue with 139 people 60 years and over with behaviours of concern for staff living in 24 care homes. A train-the-trainer approach delivered person-centred care education and support for 22 HALT (nurse) champions and 135 direct care staff, dementia management education for visiting general practitioners (GP) and pharmacists, use of an individualised deprescribing protocol for residents, and awareness-raising for the resident’s family. The HALT champions completed open-ended questionnaires and sem...

Inappropriate use of antipsychotic medications to manage Behavioral and Psychological Symptoms of Dementia (BPSD) continues despite revised guidelines and evidence for the associated risks and side effects. The aim of the Halting Antipsychotic Use in Long-Term care (HALT) project is to identify residents of long-term care (LTC) facilities on antipsychotic medications, and undertake an intervention to deprescribe (or cease) these medicines and improve non-pharmacological behavior management. LTC facilities will be recruited across Sydney, Australia. Resident inclusion criteria will be aged over 60 years, on regular antipsychotic medication, and without a primary psychotic illness or very severe BPSD, as measured using the Neuropsychiatric Inventory (NPI). Data collection will take place one month and one week prior to commencement of deprescribing; and 3, 6 and 12 months later. During the period prior to deprescribing, training will be provided for care staff on how to reduce and man...

Despite limited efficacy and significant safety concerns, antipsychotic medications are frequently used to treat behavioral and psychological symptoms of dementia (BPSD) in long-term residential care. This study evaluates the sustained reduction of antipsychotic use for BPSD through a deprescribing intervention and education of health care professionals. Repeated-measures, longitudinal, single-arm study. Long-term residential care of older adults. Nursing staff from 23 nursing homes recruited 139 residents taking regular antipsychotic medication for ≥3 months, without primary psychotic illness, such as schizophrenia or bipolar disorder, or severe BPSD. An antipsychotic deprescribing protocol was established. Education of general practitioners, pharmacists, and residential care nurses focused on nonpharmacological prevention and management of BPSD. The primary outcome was antipsychotic use over 12-month follow-up; secondary outcomes were BPSD (Neuropsychiatric Inventory, Cohen-Mansfi...

Objectives: Use of antipsychotic drugs in long-term aged care (LTC) is prevalent and commonly exceeds the recommended duration, but contributors to this problem are not well understood. The objective of this study is to provide a snapshot of the features of and contributors to prolonged use of antipsychotic medications (>12 weeks) among a sample of LTC residents. Design: We present retrospective and baseline data collected for the Australian Halting Antipsychotic Use in Long-Term Care (HALT) single-arm longitudinal deprescribing trial. Setting: Twenty-four long-term care facilities in Sydney, Australia. Participants: The HALT study included 146 older people living in 24 Sydney LTC homes who had been prescribed a regular antipsychotic medication for at least 3 months at baseline. Measurements: Detailed file audit was conducted to identify the date and indication recorded at initial prescription, consenting practices, longitudinal course of prescribing, and recommendations for revi...

Objective: Self-harm is closely associated with suicide in older adults and may provide opportunity to intervene to prevent suicide. This study aimed to systematically review recent evidence for three components of aftercare for older adults: (1) referral pathways, (2) assessment tools and safety planning approaches and (3) engagement and intervention strategies. Methods: Databases PubMed, Medline, PsychINFO, Embase and CINAHL were searched from January 2010 to 10 July 2021 by two reviewers. Empirical studies reporting aftercare interventions for older adults (aged 60+) following self-harm (including with suicidal intent) were included. Full text of articles with abstracts meeting inclusion criteria were obtained and independently reviewed by three authors to determine final studies for review. Two reviewers extracted data and assessed level of evidence (Oxford) and quality ratings (Alberta Heritage Foundation for Medical Research Standard Quality Assessment Criteria for quantitativ...

The aged care system in Australia is in crisis and people living with dementia are especially vulnerable to breaches of human rights to autonomy, dignity, respect, and equitable access to the highest quality of health care including meeting needs on account of disability. To be powerful advocates for themselves and others, people with dementia and the wider community with vested interests in quality aged care must be informed about their rights and what should be expected from the system. Prior to the Australian Royal Commission into Aged Care Quality and Safety, the Empowered Project was established to empower and raise awareness amongst people with dementia and their families about changed behaviours, chemical restraint, consent, end of life care, and security of tenure. A primary care-embedded health media campaign and national seminar tour were undertaken to meet the project aims of awareness-raising and empowerment, based on 10 Essential Facts about changed behaviours and right...